Arthritis affects 10% of the world's population. Pain, the most common symptom of arthritis, can be severe and disabling. The causes of arthritis pain are poorly understood and treatments are often ineffective, dangerous, or unavailable to many sufferers. Recent advances in the understanding of other types of pain have lead to effective specific treatments for those types of pain. Arthritis research previously has focused only on mechanisms of joint destruction and not on understanding arthritis pain. We have used mouse models of acute and chronic arthritis to study the analgesic potential of intra-articular (IA) neurotoxins (NT) for relieving arthritis pain and improving musculoskeletal function. The results of our studies with Botulinum toxin and shown that it is effective for reducing chronic arthritis pain in mice but is less effective for acte arthritis pain. We plan to use our established methods for studying arthritis pain behaviors and neuroimmuno-histochemistry to study the effects of other intra-articular neurotoxins on arthritis pain in murine models of arthritis. Our long-term goal is to discover neurotoxin therapies that could be used in combination and delivered locally with better safety and efficacy than currently available therapies for chronic arthritis pain. NT screening studies will be carried out using an acute inflammatory as well as persistent inflammatory and degenerative arthritis models. These models will be produced by injecting mouse knee joints with carrageenan, and Complete Freund's Adjuvant and by destabilizing the medial meniscus of the knee respectively. We can measure arthritis pain behaviors by observing and quantifying spontaneous pain behaviors such as nocturnal wheel-running and spontaneous nocturnal activity, as well as induced behaviors such as vocalizations, biting and fighting the handler when pressing on the painful joint and gait abnormalities due to pain using a visual video gait analysis scoring system. We will compare the analgesic effect of neurotoxins such as intra-articular capsaicin, resiniferatoxin and iodo-resiniferatoxin to standard pain medications such as morphine using these measures of tenderness, pain behavior, activity and gait. In addition to behavioral measures of pain and analgesia, we will examine the neurobiological signature of acute and chronic arthritis pain by examining markers of neural injury, inflammation and the expression of neuropeptides important for nociception in the peripheral nerves of the joint as well as in the DRG and spinal cord. We will also correlate the effect of analgesia with these changes using these same techniques. The two most effective analgesic NT will be studied in detail in the two chronic arthritis models to determine optimum effective dose and time course. The ability to test novel pain therapies such as intra-articular NTs in an animal model and to determine their effect on nervous system biology will allow us to quickly achieve our goal of identifying potentially relavent therapies for the many people with disabling chronic arthritis pain. PUBLIC HEALTH RELEVANCE: Arthritis affects 10% of the world's population. Pain from arthritis can be severe and disabling, the causes are poorly understood and treatments often don't work or are dangerous. New effective treatments are desperately needed. We have found that injecting botulism toxin into arthritic mouse joints reduces their pain. We now plan to look for other toxins that could be safely injected into joints to treat arthritis pain. We will test three new toxins by injecting the into arthritic mouse knees and measuring pain behaviors and tenderness. We will also examine nerves microscopically and with molecular techniques to look for changes due to pain or to the toxins. By discovering new toxins that reduce pain in different ways, we can help to find new treatments for humans with severe arthritis pain.